Among the treatments for cancer, chemotherapy and radiotherapy are very efficacious means for the primary elimination of leukemias, neoplasms and tumors, whereas surgery allows the excision of solid tumors. However, the prolongation of the life expectancy of patients successfully treated is often not satisfactory because of relapses.
Immunotherapy used as an antitumoral weapon derives from the need of treatments complementary to chemotherapy which, if the kinetics of first order is followed, is theoretically unable to eradicate "the last subsisting tumoral cell".
Remissions of a breast, prostate or lung carcinoma after surgery , irradiation or chemotherapy may last from 5 to 25 years, followed by relapse. As long as the immune system of the patient in remission functions normally and is not unduly solicited, the remaining tumor cells subsisting in the organism of the patient after a primary intervention will stay controlled and will not induce a relapse.
Tumor cells escape the immunological surveillance of the host by diverse mechanisms, of which the best known are, on the one hand, the scarcity of tumoral antigens that would allow for the recognition of the neoplasm by the immune system of the host and, on the other hand, the capacity of cancers to drastically reduce the immune defenses of this host. When the balance is tilted in favour of the host, at the expense of the tumor, the immunological defense mechanisms become efficient.
An immunotherapeutic intervention may reasonably find its place in a scheme of treatment only in case of recently implanted tumors (M. McKneally et al.: The Lancet, May 7 (1977), page 1003), of early diagnosed tumors of small size or of reduced numbers of cells, or after a prior intervention (surgery, chemotherapy, irradiations) has reduced the size of the tumor or the number of leukaemic cells to a proportion that would allow the immune system to regain control (N. Gross and A. Eddie: Am. Rev. Resp. Dis., 113, p. 457-464 (1976); G. Mathe et al.: Nat. Cancer Inst. Monograph No. 39, p. 165-175 (1973)).
The rejection of neoplasms by immunological means is partly based on a specific immune recognition of this neoplasm. This specific immunotherapeutic approach exploits the existence of tumor cell surface antigens recognizable by the immune system of the patient. In practice, this method may be undertaken by isolation of the cancer cells from the host and by their inactivation, followed by elimination of the tumor (surgery, radiation, chemotherapy) and the reinoculation of the inactivated tumoral cells in the patient, in order to induce an immunological reaction against the surface antigens of the tumor.
Immunotherapy based on such a system of specific recognition is only poorly efficient when applied alone. There may be production of antibodies against the neoplasm but the appearance of a delayed hypersensitivity, believed to be the main immunological method of elimination of residual tumoral cells, is rarely observed (J. Sokal et al.: Nat Cancer Inst, Monograph No. 39, p. 195-198 (1973)).
In addition, this technique is difficult to implement because it entails the collection of cancer cells from the patient (often present under the form of a solid tumor or a suspension) and the re-presentation of these cells, which must be easily inactivated by irradiation and reinoculated into the patient. Moreover, the risk that a patient may be inoculated by incompletely inactivated cancer cells is never totally excluded.
Because of these difficulties, specific immunotherapy is complemented either by an aspecific immunotherapy or else totally abandoned in favour of the latter (G. Mathe et al.: Nat. Cancer Inst. Monograph No. 39, p. 165-175 (1973)).
One form of non-specific immunotherapy has been performed for more than twenty years in the form of the antituberculous vaccine composed of live cells of an attenuated strain of the bovine tubercle bacillus, Mycobacterium bovis (strain Calmette-Guerin or BCG .RTM.). The administration of BCG, either systemically or topically, has remarkable effects on the remission of all kinds of human cancers, provided the immune system of the patient be not exhausted and the cancerous mass to be treated be not too substantial. Following a primary treatment of the patient by chemotherapy, irradiation or surgery, maintenance of the patient under remission is favoured by the administration of BCG that stimulates the aspecific immune defenses of the patient and favours the elimination of the residual cancer cells, or else at least controls their multiplication. A similar effect is observed with Corynebacterium and Nocardia, which belong to the same bacterial group (designated MHC group) as mycobacteria. Because of availability, the majority of the applications is made by BCG.
Nevertheless, the secondary (side) effects of the vaccine are not negligible: hyperthermia, chills, nausea, weakness, local infections, articular pain, swelling of wrists and other joints, vomiting and diarrhoea. The secondary effects are counteracted either by administration of salicylate, or, more frequently, by treatment of the patient in discomfort by an antituberculous drug, normally isoniazid.
Another serious objection to the use of live bacilli is the possibility of infecting the patient and to provoke a disseminated bovine tuberculosis, which may sometimes be lethal (M. McKneally et al.: The Lancet, May 7, p. 1003 (1977)) and is also usually treated by an antituberculous drug.
Moreover, great disparities have been observed in the immunotherapeutic effect of BCG, depending on source, storage and processing (J. O Bennett et al.: Cancer Res. 43, p. 4183-4190 (1983)).
The use of tuberculin (PPD, Purified Protein Derivative) for the same immunotherapeutic purpose has been attempted but has not been the object of advanced research endeavours. The motive of this failure of reseachers to explore this possible technique was in part the great variability observed in the effects produced according to the origin of the used PPD, the readily availability of BCG and, above all, the belief that the efficacy of the treatment depended on the viability of the inoculated material (an inert material such as PPD was supposedly less efficacious than live material such as BCG (J. Bennett et al.: Cancer Res., 43, p. 4183-4190 (1983)).
In addition, the hypothesis has recently been formulated that mycobacteria possess the property to induce an immunodepression in the organisms they infect: their use in a living form to potentiate the immune response of cancer patients may, if the immunological defenses of the cancerous recipient are weak, be in vain because the bacilli may in fact increase the immunodepression due to the tumor and may even provoke a generalized infection. Thus, under some conditions, the use of live material may be doubly dangerous.
On the other hand, the capacity that some mycobacterial species possess to reduce the immunity of the host would explain the variations observed in the expected immunopotentiation, when different mycobacterial strains, of variable virulence, are used.
In addition, the occasional necessity to administer antituberculous drugs when BCG is inoculated in cancer patients (McKneally et al.: The Lancet, May 7, p. 1003 (1977)) may lesd to the conclusion that the generally admitted assertion by all clinicians presently implied in this type of treatment , that live bacteria are necessary to obtain the expected immunopotentiating effects, may very well be incorrect.